FragmentScope - exploring the fragment space with learned surface representations

ABSTRACT

Abstract Exploring fragment chemical space for ligand design remains a major challenge in early stage drug discovery. This task is particularly challenging due to the small size, low specificity, and weak binding affinities of low molecular weight (MW) fragments. We present FragmentScope, a computational pipeline that uses learned protein surface fingerprints to guide fragment placement and small molecule generation. By using a contrastive learning model trained on protein-ligand interactions, we built a database of surface-fragment pairs, which enables fast and accurate fragment placement in the target protein pocket. We demonstrate its effectiveness on benchmark datasets, achieving robust placement accuracy. FragmentScope also enables the design of small molecules based on the predicted fragments ensuring synthetic accessibility. We experimentally validated Fragmentscope across 5 different targets with binding assays and structural characterization. Our approach shows high success rates in fragment discovery and yielded promising leads for designed ligands. FragmentScope offers a scalable, structure-guided approach for narrowing chemical space and identifying prospective scaffolds, accelerating the early stages of small molecule design.